The most common form of inflammatory bone destruction in humans occurs in periodontal disease (PD). PD is characterized by a chronic inflammation of the gingiva that leads to enhanced osteoclastogenesis of alveolar bone in the jaw and destruction of periodontal ligaments and other tooth-supporting structures. Initiation and progression of PD is caused by a complex ecology of anaerobic bacteria, particularly the "red complex" of Porphyromonas gingivalis (P. gingivalis), Treponema denticola and the main focus of this application, Tanerella forsythia (formerly Bacteroides forsythus). However, most of the pathology and bone destruction in PD are actually mediated by an inappropriate immune response, which leads to an imbalance in osteoclastogenesis through the combined action of inflammatory cytokines, T and B lymphocytes, and other aspects of adaptive and innate immunity. The role of T helper cells in PD pathogenesis has been controversial. Studies in humans and experimental animals have suggested a homeostatic role for T cells or even a protective role for cell-mediated immunity. There is also some evidence for suppression of T cell-mediated immunity in advanced periodontitis, and P. gingivalis exerts a downregulatory effect on CD4+ cells in mice. Conversely, mice deficient in T cells or various T cell cytokines are almost completely protected from alveolar bone destruction, and certain subtypes of T helper cells are characteristic of progressive PD lesions in humans and mice. Thus, it is still not clear how T cells contribute to host defense/pathology in PD. Part of the confusion may stem from the fact that T helper (Th) cell biology is incompletely understood. In the last few years, a major revolution in understanding CD4+ Th subsets occurred with the discovery of a new population of Th cells that secrete IL-17, and hence are termed "Th17." Th17 cells are distinct from the classic Th1 and Th2 populations, and have been found to be the major T cell mediators of host defense against extracellular pathogens but also activators of chronic inflammation in autoimmunity. We have recently demonstrated that IL-17 signaling protects against bone loss in a mouse model of PD, contrary to the intuitive prediction that IL- 17 inflammatory signaling promotes bone loss in PD. Therefore, the overall goal of this application is to assess the contributions of the three major types of Th cells to mediating alveolar bone loss and/or host defense against T. forsythia, using mouse models with targeted deletions in T cell subsets or Th-specific cytokines. Project Narrative: One of the most common forms of bone loss in humans occurs in periodontal disease (PD). PD is initiated by anaerobic bacteria such as Tanerella forsythia that colonize and invade the oral cavity in the gingival space adjacent to teeth, but it is the inflammatory events mediated by the immune system that actually triggers bone loss. The goal of this application is to define the nature of the inflammatory T cell response to periodontal bone loss mediated by Tanerella forsythia, taking into account recent advances in the field of T cell immunology.